Postpartum involution and cancer: an opportunity for ... · 2/19/2020 · Breast Cancer and...
Transcript of Postpartum involution and cancer: an opportunity for ... · 2/19/2020 · Breast Cancer and...
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Postpartum involution and cancer: an opportunity for targeted breast cancer prevention and
treatments?
Running Title: Postpartum involution and cancer review
Virginia F. Borges1, 2*#
, Traci R. Lyons1, 2*
, Doris Germain3, and Pepper Schedin
1, 4, 5#
1- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus,
Aurora.
2- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus,
Aurora.
3- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Division of Hematology/Oncology
4- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland.
5. Knight Cancer Institute, Oregon Health & Science University, Portland
*: Authors have contributed equally.
#: Co-corresponding authors
Dr. Virginia F. Borges
University of Colorado Anschutz Medical Campus
12801 E 17th
Ave, Room 8121, Mail Stop 8711
Aurora, CO 80045
303-724-0186
Dr. Pepper Schedin
Knight Cancer Research Building
Room 3024
Oregon Health and Science University
2720 S.W. Moody Avenue
Portland, OR 97201
(503)-494-9341
Conflict of Interest Statement: The authors declare that they have no potential conflicts of interest.
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Abstract
Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this
window of adverse-effect extends over two decades in women with late age first childbirth (>35 yoa). Cross-
over to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving
the most benefit. Further, breast cancer diagnosis during the five-ten-year postpartum window associates with
high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast
cancer incidence overall with varying degrees of protection by race, multiparity and lifetime duration of
lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss
the most recent data and mechanistic insights underlying these epidemiologic findings. Post-partum involution
of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed
within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic
network, extracellular matrix remodeling and increased seeding to the liver and lymph node work as
interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We also discuss a novel
mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer
potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.
Breast Cancer and Pregnancy
Cancer is an increasing complication of pregnancy worldwide, in part due to the advancing age of child-bearing
women (1-3). Cancer diagnosis during pregnancy is overall a relatively rare event, affecting about 1 in 1000
pregnancies and representing 0.1% or less of all cancers (4). Globally, the most common cancers diagnosed
during pregnancy follow the patterns of prevalent cancers in the underlying population. In Western countries,
breast, thyroid, and gynecologic cancers, as well as melanoma and lymphomas are the most common (3,5,6). In
Asia, the rate of gastric cancer is much higher, and melanoma not reported (7,8). Great progress has been made
in advancing the ability to safely treat pregnant women with excellent guidelines and reviews available across
many cancers (1,6-10). Of the cancers that affect woman during the childbearing life-window, only breast
cancer and melanoma have been implicated as being increased in frequency, specifically among postpartum
women, in comparison to age-matched peers (11). Breast cancer is globally the most frequent cancer diagnosed
during pregnancy and in the postpartum years, and therefore the most studied. However, the impact of
pregnancy on breast cancer is substantially more than the complexity of managing those diagnosed during
pregnancy and, to date, it is only breast cancer where parity status has been shown to influence prognosis. This
review will focus on the complex and varied interactions between pregnancy and breast cancer with emphasis
on breast cancer metastasis, and the unique biology underlying these interactions as observed in rodent models.
Breast cancer in women of childbearing age is a significant global problem, as there is disproportionately
increased mortality of young women’s breast cancer [YWBC], a problem exasperated in the lowest
socioeconomic countries (11). YWBC, variously defined by patient age of ≤ 35-45 years, has increased risk for
metastasis and death, with nearly twice the mortality in comparison to older women (12-15). Survival outcomes
in YWBC has lagged overall improvements in the field, with the discrepancy increasing steadily since the
1970s (16). Moreover, the incidence of distant metastases is increasing by ~2% annually exclusively in YWBC
(17,18). These adverse outcomes are often cited as due to delayed diagnosis and advanced disease presentation
in the absence of screening for women under 40 (12,19). However, in a large recent study of early stage I-II
disease, young age was an independent negative prognostic factor after adjustment for clinical, pathologic and
treatment related variables (15). Another factor cited has been the greater proportion of aggressive biologic
subtypes in YWBC, those that lack hormone receptor expression, including triple negative and Her 2
overexpressing cancers (TNBC and Her 2 respectively) (12,13,16,17). Yet, a large retrospective YWBC study
reported significantly increased two-fold risk of death with estrogen receptor positive cancer (ER+), while risk
was only modestly increased for TNBC, and was not significant in HER2+(20). In fact, the association with
negative prognosis is the strongest in YWBC with early stage ER+ tumors otherwise expected to have excellent
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outcome (12,20,21). Overall, risk factors for YWBC are not well understood, and only 10-15% of YWBC is
due to an inherited pathologic gene variant, such as the BRCA genes, p53, or PTEN (22). Lifestyle factors such
as oral contraceptive use also contribute (23). Thus, while young age at diagnosis is an independent risk factor
for relapse and death (12,15,16,20,21), current advances in the field find that heritable germline mutations do
not account for the vast majority of YWBC cases, nor find that poor outcomes are accounted for by increases in
poor prognostic tumor characteristics.
Childbearing is a natural life window that overlaps with risk for breast cancer diagnosis in women ages 20-45
and 80% of all YWBC will occur in parous women, with 50% of YWBC arising in young mothers within 10
years of their last childbirth (24). The completion of a prior childbirth is one of the more common, yet poorly
recognized, risk factors for YWBC, in part because the interaction between pregnancy and breast cancer is
complex. Since we and others find parity status impacts breast cancer incidence and outcomes in women
diagnosed ≤45 years of age (24-26), we define YWBC as cases diagnosed at age 45 and under. Thus defined,
YWBC accounts for ~13% of all breast cancer in developing countries and higher percentages in lower
economic countries (27,28). Worldwide estimates of PPBC range from ~150,000 to 350,000 cases annually,
based on global breast cancer (27,28) or childbirth rates (24), respectively (Text Box 1).
Pregnancy both promotes and protects against breast cancer (29-31). All parous women are under a 10-30%
increased risk of developing breast cancer for at least a decade after childbirth in comparison to nulliparous
young women, with older age at first birth increasing the magnitude of risk (31). Overtime, a cross-over effect
dissipates this risk and the prior childbirth subsequently protects against breast cancer if the woman began her
childbearing before age 35 (30,31). What factors other than parity also influence the incidence of breast cancer
in postpartum women [postpartum breast cancer or PPBC] and YWBC remain under investigation. Increased
breast density, radiographically identified as heterogeneously dense or extremely dense tissue on
mammograms, elevates breast cancer risk 4-fold or higher, and equally affects risk in women of all ages
(32,33). In women age 45 and under, higher breast density is seen with nulliparity and later onset of
childbearing, which are life factors known to increase breast cancer risk (34,35). African-American women,
who face a high incidence of YWBC, have higher breast density when multiple qualities of breast density are
incorporated across age and parity group, as compared with white women (36). Further on in this review,
mechanistic links between parity, lactation and active collagen deposition within the breast are described.
These data offer leads to an improved understanding of the role of breast density in PPBC, and highlight the
need for additional studies.
Overall, the postpartum life window is under-recognized as a time of higher risk for early onset breast cancer
(Figure 1). Moreover, cancers diagnosed during this window of increased risk also carry worse prognosis
(24,26,30,37-39). Women diagnosed and treated during their pregnancy have usual prognosis, based on stage
and biology of the tumor (26,30). Conversely, women diagnosed postpartum have significantly increased risk
for metastatic recurrence (37-39), which is highest among women diagnosed within 5 years of last childbirth
but extends to ten years postpartum (37). Further, the risk for metastasis is 3-5-fold higher for postpartum stage
I/II cancers, regardless of ER status (37). Recognition of this extended risk window for both ER+ and ER-
cancers is critical with respect to understanding the underlying biology of postpartum breast cancer, as well as
for identifying YWBC patients at highest risk of recurrence. This later point is highlighted by the fact that
when outcomes are grouped as pregnancy-associated breast cancers (pregnant cases plus 1-2-year postpartum
cases) and compared with an unselected group of age matched YWBC, the differences in outcome are obscured
(24). Thus, the definition of PPBC matters, as it effects the interpretation of outcomes data and ultimately
patient care.
Tumor promotion during postpartum breast involution
The fact that a postpartum diagnosis in young women strongly associates with worse outcomes has led to the
concept that a pro-metastatic biology is present in the postpartum breast (31). A unique breast biology specific
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to postpartum women that may account for the increased risk of metastasis is mammary gland involution (40).
Mammary tissue expands ~10 fold during pregnancy in preparation for lactation; then, mammary gland
involution occurs when milk production ends, either after birth in the absence of nursing, or after weaning (41).
In adult rodents and women, postpartum mammary gland involution is reported as the most dramatic example
of physiologic tissue remodeling to occur in the adult, as 80-90% of the alveolar mammary epithelium is
removed by programmed cell death (42,43). Direct support for the hypothesis that postpartum mammary gland
involution is tumor promotional comes from preclinical studies. Using xenograft and isogenic tumor transplant
models, the normal tissue microenvironment of the actively involuting mammary gland has been demonstrated
to increase breast cancer tumor take and metastasis compared to the mammary microenvironment of the
nulliparous or parous host (44-46).
There are several mechanisms observed in the involuting gland that may drive metastasis. The death of the
alveolar mammary epithelium is coordinated with inflammation (47,48), lymphangiogenesis (44), fibroblast
activation (49), and collagen 1, fibronectin, and tenascin-C rich matrix deposition (49,50)--all stromal attributes
that mirror wound-healing and are causal to cancer outcomes. Importantly, the findings of a similar pro-tumor,
breast involution program being present in the breast tissue of young, recently pregnant women offers a
plausible link between involution and PPBC outcomes (41,44). The potential mechanisms by which the
transient event of normal mammary gland involution impacts long term outcomes in postpartum patients is
likely multifactorial. Rodent models of PPBC reveal that occult tumor cells are “released” into the activated
mammary stromal compartment during weaning-induced alveolar collapse, where they access the vasculature,
disseminate, and set up micro-metastases in distant organs (44,45). Additionally, expansion of the lymphatic
vasculature occurs during involution allowing for increased tumor cell trafficking in the lymph vessels and
seeding of the lymph node (44,51). This involution-specific mammary lymphangiogenesis is consistent with
the observed increased lymph node involvement in PPBC patients compared to age matched nulliparous
patients (26,44).
There is also a distinct visceral pattern of metastasis in PPBC that suggests circulating tumor cells released
from the involuting mammary gland have additional metastatic advantages. In postpartum patients, a ~3-fold
increase in liver metastasis but not lung, brain or bone is reported (52). This metastatic pattern is consistent
with a uniquely hospitable “soil” in the liver of postpartum women. This novel hypothesis is supported by
rodent studies, where the postpartum liver is found to support breast cancer metastasis. The basis of this liver
specific metastatic preference appears to be due to a functional link between the mammary gland and liver that
is established to support lactation. Specifically, in preparation for lactation and throughout lactation, the rodent
liver doubles in size and increases anabolic metabolism (52). Upon weaning, the liver undergoes a regression
process that displays the hallmarks of mammary gland involution: parenchymal (hepatocyte) apoptosis,
catabolic metabolism, ECM remodeling including deposition of collagen I, tenascin-C and fibronectin, and
immune cell influx suggestive of immune tolerance (52). Intraportal tumor cell delivery (53) to the involuting
liver leads to increased metastatic outgrowth compared to livers of nulliparous murine hosts, data consistent
with the establishment of a pro-metastatic liver niche following weaning (52). While the molecular
mechanisms that mediate the functional coordination between the lactating mammary gland and liver are
unknown, and evidence for post-weaning liver involution in women not reported, continued investigation into
site specific metastasis patterns in YWBC and PPBC is warranted.
In rodent models, involution and PPBCs are also marked by an immune phenotype typically associated with
immune tolerance and T cell exhaustion. Specifically, within the lymphoid lineage, Th-17, Th-2 and Treg
skewed T cells are elevated (48,54,55), with functional evidence for active suppression of T cell proliferation
limited to the involution window (48). Within the myeloid lineage, there are observed enrichments in
CD11b+/F480+ myeloid derived suppressor cells (MDSC) (48) and M2-skewed macrophages, which likely
suppress T cell activation through secretion of IL-10, a Th1 inhibitory cytokine, and by depleting arginine from
the tissue microenvironment (54,56). These macrophages exhibit characteristics that are similar to tumor
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associated macrophages, which have been identified to promote tumor cell invasion and extravasation (57,58).
Additionally, the involuting gland is enriched for mammary macrophages similar to the recently identified
tumor associated Podoplanin Expressing Macrophages or PoEMs (59). Within tumors, PoEMs promote
metastasis via production of collagen and loosening of the lymphatic vasculature, allowing for tumor cells to
enter the lymphatics (59). Histologic evidence confirms the presence of increased lymphatic associated
macrophages in PPBC patients (51). Molecular analysis of the lymphatic vessels and macrophages during
involution and in models of PPBC has also revealed expression of programmed death ligand-1 (PD-L1), similar
to what is observed during peripheral tolerance (60-63). Since PD-L1 engagement of its receptor PD-1 inhibits
T cell responses through activation of pro-apoptotic signaling, these data suggest that lymphatic-mediated
immune avoidance (64-66) is one mechanism by which involution promotes PPBC. Consistent with this,
murine PPBC tumors are particularly sensitive to anti-PD-1 therapy, which resulted in regression of the
lymphatics and decreased T cell exhaustion (60). Collectively, these data provide several plausible mechanisms
for increased metastases in postpartum patients that includes immune avoidance, increased tumor cell escape
from the primary site, increased lymphatic network for dissemination and maintenance of immune avoidance,
and increased seeding in the liver, all of which may be targetable with clinically available therapies.
In addition to involution creating favorable stromal microenvironments for the expansion and spread of tumor
cells, a second mechanism by which involution might durably promote breast cancer and poor outcomes is
through tumor cell imprinting. Several lines of evidence suggest that tumor cells and mammary epithelial cells
are permanently altered after a pregnancy/lactation/involution cycle. Firstly, parity induced mammary stem cell
populations, with similarities to tumor cells, are maintained after pregnancy and expand with multiparity in
rodents (67,68). Secondly, mRNA analysis of normal mammary tissues from parous women within 10 years
postpartum reveals stable changes in gene expression associated with inflammation, ECM, and hormone
receptor signaling (69,70). Multiple studies have also identified programs of postpartum involution that are
mirrored in tumor cells and in the TME after involution (71). Specifically, collagen, COX-2, SEMA7A, and
lymphangiogenesis are described in involuting mouse mammary tissue, in normal adjacent mammary tissue
from postpartum patients, and in PPBC tumors in murine models (44,46,51,56,72). Importantly, NSAID
inhibition reveals that COX-2 activity is required for metastasis in murine postpartum hosts; additionally,
NSAIDs reverse aspects of gland desmoplasia, lymphangiogenesis and T cell suppression, including re-
establishment of Th1 cytokine production and T cell accumulation at the border of postpartum tumors (45,55).
Finally, SEMA7A promotes multiple aspects of tumor progression during involution including
lymphangiogenesis, mesenchymal phenotypes, as well as tumor cell invasion and survival (51,73). Moreover,
knockdown of SEMA7A reduces collagen deposition and COX-2 expression in pre-clinical models of PPBC
(74) and knockdown of COX-2 similarly results in downregulation of SEMA7A (73), suggesting a relationship
between these two signaling molecules. Thus, both COX-2 and SEMA7A represent additional avenues that can
be explored for the prevention and treatment of PPBC.
While evidence for tumor cell imprinting in PPBC is still emerging, the study of transcriptional regulators of
normal mammary gland involution may also offer insights. Transcriptional regulators with known pro-and anti-
tumor activities orchestrate the balance between epithelial cell survival and death during involution. For
example, CEBPD, a member of the C/EBP transcription factor family, is an important regulator of involution
(75,76). In CEBPD gene knockout studies in mice, CEBPD was found to support pro-apoptotic signaling of
involution as well as stromal remodeling, particularly via upregulation of matrix metalloproteinases (75,76).
Conversely, SIM2s, a transcription factor with known tumor suppressive activities, is required for lactogenic
differentiation. Continued expression of SIM2s delays involution by decreasing Stat3 and NFKB signaling
(77), two pro-apoptotic signaling pathways critical for involution (78-82). Interestingly, SIM2s was recently
shown to downregulate COX-2 and loss of SIM2s promotes mammary tumorigenesis via upregulation of EMT
and invasion (83,84). Importantly, inhibition and knockdown of COX-2 reduces invasion and restores SIM2
expression in breast cancer cells and xenografts (83,84). An intriguing prospect is that PPBC will be imprinted
by the transcriptional programs of involution, such as CEBPD gain and SIM2s loss, which may identify
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additional novel pathways of vulnerability in PPBC. Indirect evidence for this hypothesis has been reported, as
gene signatures associated with normal mammary gland involution (85,86) correlate with aggressive triple
negative and inflammatory breast cancers and predict worse breast cancer specific survival in breast cancer
overall (87,88).
Mechanistic insights into the protective effect of lactation
Lactation is identified as an important factor affecting incidence of breast cancer in both YWBC and
postmenopausal diagnosis. Breastfeeding has a significant protective effect against triple negative breast
cancers in African-American women and BRCA1 mutation carriers, and overall breastfeeding reduces risk for
white women and ER+ subtypes, particularly for a postmenopausal diagnosis (23,37). A recent meta-analysis of
50,302 women from 47 independent studies revealed that extended lactation is protective against breast cancer,
with risk reduction being dependent on cumulative lifetime duration, and independent of maternal age or
multiparity. In this study, amongst the parous women with breast cancer, fewer had ever breastfed and for those
who did, the average time of breastfeeding was shorter (9.8 months) when compared to parous women without
breast cancer (15.6 months)(89). Further, from this study the authors suggested that extension of breastfeeding,
by 12 months per child, may reduce the risk of breast cancer by more than half, since they reported a reduction
from 6.3 breast cancer cases per 100 women to 2.7 breast cancer cases per 100 women (89). Additionally, the
length of lactation was found to be reduced in high-income countries relative to low-income countries, which
may partially explain the increased incidence of postmenopausal breast cancer in high-income countries (27,90)
Therefore, understanding how lactation impacts risk of breast cancer, and whether it counters adverse effects of
involution is critical.
Insulin-like growth factor 1 (IGF-I) protects mammary epithelial cells from apoptosis during lactation (91-93).
Insulin-like growth factor binding protein-5 (IGFBP-5) prevents activation of IGF receptor by titrating away
IGF-I and II (94). Thus, IGFBP5 was proposed as a mediator of involution, and IGFBP5 knockout mice exhibit
delayed involution (95-98). Therefore, the effect of IGFBP-5 on IGF signaling may be especially important
during involution. In agreement with the importance of limiting IGF signaling in this setting, the protective
effect of pregnancy is associated with reduced expression of IGF receptor (94). IGFBP-5 is itself negatively
regulated by the protease pappalysin-1 (PAPP-A)(99-103), which is overexpressed in the vast majority of breast
cancers (104), and decreased expression of IGFBP-5 is associated with higher risk of developing breast cancer
(105,106). Analysis of transgenic mice with mammary specific expression of PAPP-A revealed development of
mammary tumors exclusively following pregnancy (107,108). Importantly, the length of lactation drastically
impacted the rate of PPBC in these mice (107). Transgenic females that had an abrupt cessation after 2 days of
lactation developed PPBC; in contrast, females that fed their pups for extended periods of time did not (107).
This observation suggests that extended lactation is protective against the oncogenic effect of PAPP-A.
Mechanistically, glycoproteins Stanniocalcin-1 (STC1) and -2 (STC2) can act as inhibitors of PAPP-A
(109,110) and the protective effect of lactation is associated with the expression of STC1 and STC2 (107).
Further, STCs are produced by the ovaries and can be detected at high levels in the serum only during
pregnancy and lactation, but not during involution, suggesting a possible systemic role for STCs in tumor
suppression during pregnancy and lactation (111).
Interestingly, a recent study reported that abrupt interruption of lactation in mice induces an increase in markers
of inflammation. This finding is consistent with the role of PAPP-A in involution and the importance of the
STCs to inhibit PAPP-A activity, since PAPP-A is known to be induced by inflammatory cytokines such as IL-
6, TNF, IL-1, IL-4, and TGF-(112). Abrupt cessation of lactation was also associated with increased
cellular proliferation and deposition of collagen as well as expansion of the luminal progenitor cells in the
mammary gland compared to mice where cessation of lactation was gradual (113). The latter observation in
mice that abrupt cessation promoted the expression of estrogen and progesterone receptors is in agreement with
the protective effect of breastfeeding against ER+ breast cancer in women (23,37). The authors also reported
ductal hyperplasia four months postpartum in mice where lactation was abruptly interrupted (113). It is
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currently unknown whether this holds true in humans. However, in human breasts undergoing gradual weaning,
lobules undergoing apoptosis and tissue inflammation are observed adjacent to non-inflamed lactational lobules
(41,114,115) (Supplemental Figure 1). These observations suggest that, even with gradual weaning, tumor
cells could be exposed to a pro-tumor microenvironment, and therefore by extrapolation, appears that gradual
weaning would not completely protect a woman’s breast from the protumorigenic aspects of involution.
Additional studies are necessary to determine how gradual and abrupt cessation of weaning interact with
involution and impact the breast tissue microenvironment, and subsequent breast cancer risk and outcomes.
Of note, increased deposition of collagen during involution induces COX-2 expression, which drives PPBC
metastasis (45) and the mammary glands of involuting PAPP-A transgenic mice following an abrupt cessation
of lactation, exhibit an even higher level of collagen (107). Additionally, PAPP-A is dependent on collagen for
its activation (107), thereby offering a mechanism by which PAPP-A transgenic mice only develop mammary
tumors following pregnancy--as passage through involution and increased collagen deposition during this phase
is required for its activation. In a more recent study, PAPP-A was found to activate the collagen receptor DDR2
(108), which promotes metastasis via activation of the ERK-Snail axis (116). Thus, the activation of DDR2 by
PAPP-A offers an additional mechanism by which PPBCs are associated with increased metastasis and worst
outcomes. Consistent with this, deletion of DDR2 by CRISPR was shown to abolish the pro-invasion effect of
PAPP-A (108) and a PAPP-A/Snail/Collagen signature was found to identify patients at higher risk of
metastasis (108). Collectively, these data suggest that lactation or extended lactation may be protective against
breast cancer via suppression of PAPP-A and downregulation of collagen mediated pro-tumorigenic signaling
in the mammary gland.
Concluding remarks
Postpartum breast cancer is a global health threat that affects ~150,000-350,000 young mothers annually,
placing them at increased risk for metastasis and therefore death. Since lactation and postpartum breast
involution are both predictive for breast cancer, the postpartum life window is a free, readily available
“biomarker” for assessments of PPBC risk and outcomes. The insights gleaned from mechanistic studies of
lactation and involution offer important avenues forward. Specifically, the roles of COX-2, SEMA7A, and
PAPP-A as putative oncogenes for PPBC, and the identification of lactation-induced SIM2s, STC-1 and STC-2
as inhibitors of PPBC-associated oncogenes, provide immediate leads for targeted prevention and treatment
interventions (Figure 2). To continue to advance PPBC prevention, additional programs to facilitate lactation
globally are needed. Also, research efforts to identify women at high risk for PPBC will support future
prevention trials. Finally, investigations into the unique molecular vulnerabilities of PPBC are anticipated to
yield rich venues for targeted therapeutics. Combined, these strategies will address the unmet clinical needs of
young women at risk for PPBC, a population in dire need of improved prevention and treatment strategies.
Acknowledgements
This work was supported by the following grants: PS and VB received R01CA169175; TL received
R01CA211696 and RSG-16-171-010CSM from the American Cancer Society; DG received a Precision and
prevention Initiative grant from the Breast Cancer Research Foundation; PS received a grant from the Willard
L. Eccles Charitable Foundation.
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14
TEXT BOX #1
Metrics related to reproductive history are not commonly included in breast cancer clinical data sets, such that the number of breast cancers that meet the definition of PPBC is currently derived from best estimates. One approach to estimate global burden of PPBC is to utilize data obtained from developed countries, which show that ~13% of all breast cancers are YWBC (27, 28) and that ~50% of these cases have likely completed a pregnancy within 10 years of their diagnosis (29). This approach results in a global estimation of ~130,000 PPBC cases per year. An alternative approach is to determine the incidence of PPBC cases per completed pregnancy (again relying on data from developed countries) and then determining global burden based on number of pregnancies worldwide. Best estimates for PPBC cases in the US for 2015 is ~13,000. Based on 4.5 million U.S pregnancies/year, this would predict a PPBC incidence of 0.0028% (one in every ~350 pregnancies). With ~130,000,000 live births globally per year, this estimation approach predicts 364,200 cases of PPBC worldwide (https://www.un.org/en/development/desa/population).
Figure 1. Graphical presentation of the associations between pregnancy and lactation with breast
cancer risk and outcome. While pregnancy confers long term protection in young first mothers, all
mothers experience a transient early risk for breast cancer which extends long term in older mothers.
Additionally, in those who do not lactate this risk is also increased and there is evidence that
prolonged lactation can also decrease long term risk for breast cancer. Finally, if breast cancer is
diagnosed in the postpartum decade there is an increased risk for metastasis and death from breast
cancer compared with nulliparous or older women, which is not seen among cases diagnosed during
pregnancy.
Figure 2. Model of how lactation, postpartum involution and epithelial cell imprinting of parity intersect
to impact incidence and outcomes in postpartum breast cancer (PPBC). Physiologic involution
(middle panel) , which is mediated in part by pro-tumorigenic TGFbeta, COX-2, SEMA7A and
collagen dependent signaling, shares numerous attributes with pro-tumor wound healing, including
immune cell infiltrate, immune tolerance, and lymphangiogenesis, resulting in involution being a risk
window for poor prognostic breast cancer. Upregulation of molecules with known tumor suppressive
functions are present during lactation (left panel) and abrupt cessation of lactation exasperates
involution associated programs of inflammation, which contributes to abnormal expression of PAPP-A
during involution. The increased deposition of collagen during involution acts to enhance the
proteolytic activity of PAPP-A against IGFBP-5 leading to increased IGF and collagen receptor DDR2
signaling and tumor promotion. In contrast, prolonged or gradual cessation of lactation promotes the
accumulation of stanniocalin 1 and 2 (STC1, 2), which act as inhibitors of PAPP-A, reducing tumor
progression. Mammary epithelial cells are also imprinted by undergoing a reproductive cycle (right
panel), which possibly accounts for the increased tumor risk and progression that are elevated for at
least 10 years post childbirth. Image courtesy of Sarah E Tarullo, PhD (University of Colorado).
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Metrics related to reproductive history are not commonly included in breast cancer clinical data sets,such that the number of breast cancers that meet the definition of PPBC is currently derived from bestestimates. One approach to estimate global burden of PPBC is to utilize data obtained from developedcountries, which show that ~13% of all breast cancers are YWBC (27, 28) and that ~50% of these caseshave likely completed a pregnancy within 10 years of their diagnosis (29). This approach results in aglobal estimation of ~130,000 PPBC cases per year. An alternative approach is to determine theincidence of PPBC cases per completed pregnancy (again relying on data from developed countries)and then determining global burden based on number of pregnancies worldwide. Best estimates forPPBC cases in the US for 2015 is ~13,000. Based on 4.5 million U.S pregnancies/year, this would predict aPPBC incidence of 0.0028% (one in every ~350 pregnancies). With ~130,000,000 live births globally peryear, this estimation approach predicts 364,200 cases of PPBC worldwide(https://www.un.org/en/development/desa/population).
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Decreased
Cross over effect to long term protection for young first mothers
Prolonged lactation
Increased
Transient early risk
Long term increased risk for older mothers
No lactation
Metastasis and death if BCdiagnosed in postpartum decade
Breast cancer risk over time
Pregnancy &childbirth
Lactation
Involution
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Lactation
Milk
Mammary epithelial cell
Myoepithelial cell
Dying epithelial cell
Apoptotic cell/fragments
Basement membrane
Fibroblast
Collagen
Macrophage
SIM277
CEPBD75,76
STAT579,86,85
Involution
Gradualweaning
Inflammation85,86
Immune tolerance60
Lymphangiogenesis44,51,60
<5 Parous
TGFa112
Collagen 131,46
ANGPT169
CCL2169
ESR269
LBP69
SAA1/269
SEMA7A51
TIMP269
PPBCmetastasis
?
?
COX-244,45,72
Collagen45,56,72,108,113
PAPP-A104,107,108
cleavage
SEMA7A51
NSAIDs55
STC-1110
STC-2109
IGFBP-594,100–103
IGF signaling94
DDR2 signaling108
54–56,72,
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Published OnlineFirst February 19, 2020.Cancer Res Virginia F. Borges, Traci R. Lyons, Doris Germain, et al. breast cancer prevention and treatments?Postpartum involution and cancer: an opportunity for targeted
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